4.12 - Immune Response to Infection Flashcards
1
Q
What are the steps of the immune response to infection?
A
- microbial detection - bacteria, fungi, protozoa, viruses, microbiota
- innate immune response - epithelia, phagocytes, NK cells, innate lymphoid cells
- adaptive immune response - lymphoid tissues, T and B lymphocytes, antibodies, cytotoxic T cells
- memory response - memory T and B cells, quick and specific response, lifelong immunity
2
Q
Leukocytes and the soluble mediators they release
A
- antibodies - B cells
- cytokines - T cells, large granular lymphocytes, mononuclear phagocytes
- complement - mononuclear phagocytes
- inflammatory mediators - basophils, mast cells, platelets
- interferons & cytokines - tissue cells
3
Q
What are the four different pathogen niches during infection?
A
- extracellular e.g. Staphylococcus, Streptococcus, Candida, microbiota, worms
- surface adherent e.g. enteropathogenic & enterohaemorrhagic E. coli
- intracellular vacuolar (that occupy specialised compartment in host cell e.g. modified lysosome or ER) e.g. Salmonella, Chlamydia, Legionella, Coxiella, Plasmodium
- intracellular cytosolic e.g. viruses, Listeria, Burkholderia, Mycobacterium
4
Q
How does an immune response to infection start?
A
- tissue damage (e.g. injury / by toxins)
- molecular detection of microbes - wrong thing in the wrong place at the wrong time
- then, intercellular communication happens e.g. interleukins
- this leads to priming of the adaptive immune response
5
Q
How does an immune response to infection end?
A
- clearing infection
- stopping inflammatory cytokine production - more production of these can lead to tissue damage
- repairing tissue damage
- remembering the infection - immune memory
6
Q
What are the components of innate immunity?
A
- fast acting, first line of defence, germline encoded receptors
- physical barriers - skin, mucous, epithelial cells
- humoral - complement, lectins, pentraxins, antimicrobial peptides
- cellular - neutrophils, macrophages, dendritic cells, NK cells
7
Q
What are the components of adaptive immunity?
A
- slower but long-lasting, variable receptors that mature over time (DNA recombination)
- humoral - antibodies, complement
- cellular - cytotoxic T cells, T helper cells, T regulatory cells, B lymphocytes and plasma cells
8
Q
What are the differences between innate and adaptive immunity?
A
SPECIFICITY:
- innate - for structures shared by classes of microbes (PAMPs)
- adaptive - for structural detail of antigens, may recognise nonmicrobial antigens
NUMBER OF MICROBIAL MOLECULES RECOGNISED:
- innate - about 1000 PAMPs
- adaptive >10^7 antigens
RECEPTORS:
- innate - encoded in germline, limited diversity
- adaptive - encoded by genes produced by somatic recombination of gene segments, greater diversity
NUMBER AND TYPES OF RECEPTORS:
- innate <100 different types of invariant receptors
- adaptive - only two types of receptors (Ig and TCR), with millions of variations of each
DISTRIBUTION OF RECEPTORS:
- innate - nonclonal - identical receptors on all cells of the same lineage
- adaptive - clonal - clones of lymphocytes with distinct specificities express different receptors
9
Q
What are there differences between in the innate and adaptive responses?
A
- timing of the response
- cell types
- receptors and ligands
- cytokines and chemokines
- molecular effector machineries
- both arms of the immune system together provide sterilising immunity and long-term memory
10
Q
What happens when resting cells encounter a pathogen?
A
- resting cells come into contact with pathogen and recognises it through ligands or pathogen activities
- resting cell puts gene expression changes into action which means new genes expressed and translated into proteins
- these proteins include antimicrobial molecules that are directly toxic to pathogen
- proteins also include interleukins, chemokines, interferons etc and some are released from cell to communicate with neighbouring cells that haven’t encountered pathogen directly to make them ready
- these molecules also act on primary infected cell in autocrine manner, resulting in resting cell becoming activated and ready to tackle pathogen
11
Q
What are some examples of molecules acting on primary infected cell and activating them?
A
- naive T cells that become finetuned by antigen become CD4 or CD8 cell
- macrophage that detects LPS from gram negative bacteria becomes an activated macrophage
12
Q
What are the first responders to site of injury?
A
- neutrophils are first to respond (short-lived, 6h) followed by monocytes that differentiate to become macrophages
- naive cells become activated upon interaction with microbes
- phagocytes control infection and limit/repair tissue damage
13
Q
Why is uncontrolled activity of phagocytes bad?
A
- in granulomas and similar situations they can release excessive cytokines
- leads to more tissue damage than controlling infection
- excessive inflammation and inappropriate adaptive immunity
- tissue damage and blocked resolution of inflammation
14
Q
How do phagocytes and other immune cells identify the class of pathogen?
A
- bacteria - cell wall components e.g. LPS in E. coli
- fungi - beta glucans are common fungi surface molecules and receptors like dectin-1 recognise these and signal through SRC tyrosine kinases
- viruses - viral DNA/RNA in cytoplasm detected through various molecules, receptors and sensors
15
Q
What type of immune response does bacteria produce?
A
Live E. coli elicits immune response:
- inflammatory cytokines produced (e.g. IL-1beta that causes fever)
- antimicrobial genes (directly toxic to bacteria)
- metabolic genes (help macrophage cope with demand)
- immunomodulatory genes (so adaptive immune system appropriately primed)
Dead E. coli results in no immune response
- macrophage tries to resolve inflammation
16
Q
What type of immune response do fungi produce?
A
- proinflammatory cytokines
- antimicrobial genes
- metabolic genes
- immunomodulatory genes
17
Q
What type of immune response do viruses produce?
A
- interferon production (interferes with viral replication)
- proinflammatory cytokines
- antiviral genes
- immunomodulatory genes
18
Q
What is the role of macrophages in the immune response?
A
- macrophages are tissue resident or circulatory (from bone marrow)
- macrophage activation = expression of many new genes - induced by microbes and cytokines
- ‘alternatively’ activated macrophages are anti-inflammatory
19
Q
What do activated macrophages display enhanced?
A
- phagocytosis and migration
- cytokine/chemokine production
- expression of cell surface molecules
- antimicrobial activity
- antigen presentation and T cell activation
20
Q
What is crosstalk between macrophages and lymphocytes during infection by intracellular pathogens?
A
- macrophage becomes infected with pathogen and after recognising this, it releases a set of cytokines e.g. IL-12, 18, 1, 6, TNF
- these are recognised by T lymphocytes which produce IFN-gamma (type 2 interferon) which acts on macrophage and produces a number of new genes that are directly toxic to the pathogen
- macrophage is activated and kills phagocytosed microbe
- IFN-gamma crucial in killing and controlling Salmonella and mycobacterium infections
21
Q
What are interferons?
A
- interferons are special cytokines - three types
- detection of viruses or gram negative bacteria results in their production
- have direct antiviral activities
- immunomodulatory roles - enhanced T cell responses (higher MHC expression), anti-inflammatory actions, tissue repair
22
Q
What are type I interferons?
A
- IFN alpha/beta
- signalling on target cells results in expression of antiviral genes including:
- nucleases
- inhibitors of viral entry, uncoating, replication and exit
- inhibitors of protein translation
- every primary infected cell can produce type I IFN which can act on neighbouring cells to make them more able to resist viral infection
22
Q
What are type II interferons?
A
- IFN gamma
- only produced by lymphocytes
- every single cell can respond to type I and II IFNs
- expression of antiviral genes
- promote antibacterial immunity
- Th1 skewing
23
Q
What are type III interferons?
A
- IFN lambda
- response and gene expression changes is similar to type I IFN but expression pattern is more limited
- only produced at epithelial surfaces but type I can be produced deeper in tissue as well
- promote antiviral responses
- mucosal immunity
24
How are virus-infected cells killed?
- killed by actions of cytotoxic T lymphocytes (CTLs) or NK cells
- NKs detect downregulation of MHC on surface of virus-infected cells so target this and kill it
- CTLs and NKs directly kill infected cells (contact-dependent) through granzymes which cause apoptosis
- cell death removes viral replicative niches
- host cells infected with intracellular bacterial pathogens also undergo forms of cell death (contact-independent)
25
What are the soluble effector mechanisms of innate immunity?
- complement mediated bacterial destruction
- lectin-binding to neutralise cell attachment or entry
- iron chelation (siderophores) to prevent replication
- antibiotic-like peptides
26
What are the cellular effector mechanisms of innate immunity?
- reactive oxygen and nitrogen radicals (made by phagocyte oxidase and iNOS respectively - these genes are never present in naive cells and only expressed when pathogen encountered)
- acidification and digestion within phagosomes
27
How are T cells activated?
- activated macrophages and DCs present antigens in combination with MHC-I/II to T cells
- cytokines produced by APCs produce a suitable milieu for T cell activation e.g. IL-12 promotes T cell replication
- T cells then provide cytokines that activate phagocytes e.g. IFN-gamma upregulates MHC-II expression for antigen presentation
- they also produce cytokines that work in an autocrine way
- responses are specific to general class of pathogens
28
How are dendritic cells better able to respond to viral infections than macrophages?
They produce a lot of type I IFN during infection
29
How do T cells help B cells produce antibodies?
- APCs activated by infection and cytokines
- cognate MHC presents foreign antigen to T cell which becomes activated to Th cell
- Th helps activate B cell with the correct BCR which produces antibodies against antigen
- antibody-mediated enhanced microbial response - phagocytosis (opsonisation) and complement activation
30
What are the two main T cell types?
- Th1 cell (CD4 T cell) - produced during bacterial infections that produce IFN-gamma and other cytokines that promote inflammation, phagocytosis and killing of microbes
- Tc cell (CD8 T cell) - produced during viral infections and will directly kill virus infected cells leading to apoptosis of host cell, removing viral replicative niches
31
What are some T cell functions?
- phagocyte activation - T cell derived cytokines activate phagocytes --> enhanced killing of pathogens & inflammation
- direct killing of infected cells - removal of replicative niches
- B cell activation - antibody production and affinity maturation
- innate lymphoid cells (gamma delta T cells) - reside in mucosal surfaces and are a type of early responders to infection (act independently to MHC)
32
Microbe-specific phagocyte responses
- Th1 --> IFN-gamma --> macrophages --> macrophage activation --> autoimmunity, chronic inflammation - intracellular pathogens
- Th2 --> IL-4,5,13 --> eosinophil and mast cell activation, alternative macrophage activation --> allergy - helminths
- Th17 --> IL-17,22 --> neutrophil recruitment and activation --> autoimmunity, inflammation - extracellular bacteria and fungi
33
What is the overall sequence of the immune response?
1. naive phagocyte encounters pathogens --> cytokines that act on itself and neighbouring cells
2. results in gene expression in original phagocyte which results in interleukins, interferons being made = activates it --> APC, MHC
3. T and B cells recognise antigens = proliferation to create a clonal population which differentiates into plasma cells that make antibody for B cells, and different classes of helper T cells like Th1/2/17 for T cells
4. small amounts of the clonal population of both B and T cells reside in tissues as memory lymphocytes that can become rapidly activated upon a second infection to divide into more Th cells or plasma cells
34
What is the difference in serum antibody titre between first and second infections of the same antigen?
- secondary response is quicker
- more antibody made
- level of antibody after infection reduces slower and stays at a higher level
35
What is the impact of age on the immune response?
- as age increases, immune response gets weaker
- mainly due to reduced thymic output - thymic involution
36
Genetic and acquired immunodeficiencies
- complement - various complement genes
- leukocyte adhesion - genes involved in migration and adhesion
- chronic granulomatous disease - loss of ROS production
- Chediak-Higashi syndrome - compromised lysosomes
- cytokine genes and their receptors - loss of cell-to-cell communication
- severe combined immunodeficiency (SCID) - severe reduction and function of T and B cells
- X-linked agammaglobulinaemia - decreased serum IgG of all types
- HIV - reduced CD4 T helper cells
- irradiation and chemotherapy - loss of bone marrow precursors
- immunosuppression (graft rejection/chronic disease) - depletion or impairment of lymphocytes
37
Summary of immune response to infection
- first responders detect infection and try to control microbial growth and spread
- chemokines further recruit immune cells, cytokines trigger inflammation and activate cells
- DCs, macrophages and B cells present antigens and activate T cells, which undergo differentiation
- specialised B and T cells together contribute to humoral and cellular immunity to pathogen classes
- genetic and environmental factors can predispose individuals to infections
